Substituted s-triazines



United States Patent 3,522,255 SUBSTITUTED s-TRIAZINES Werner Heimberger, Hanan am Main, Germany, assignor to Deutsche Goldund Silber-Scheideanstalt vormals Roessler, Frankfurt am Main, Germany No Drawing. Filed Oct. 31, 1966, Ser. No. 594,647 Claims priority, application Germany, Oct. 30, 1965, D 48,552 Int. Cl. C07d 55/18, 55/20 US. Cl. 260-249.9 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula wherein R and R can be the same or different and are selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms and hydroxy alkyl of 1-6 carbon atoms; Y is selected from the group consisting of and and

wherein Hal is a halogen atom, preferably chlorine, R is selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms and alkyl of 1-6 carbon atoms substituted by -OH, --OR -NHR -N(R or a halogen atom, R and R have the same significance as R and R and furthermore may be closed to a ring, possibly with the inclusion of a further heteroatom, such as piperazine, piperidine, phenoxazine, 9,10-dihydrophenazine or morpholine ring and R is selected from the group consisting of aryl such as phenyl and alkyl of 1-6 carbon atoms, R taken individually are aryl or alkyl of 1 to 6 carbon atoms and taken together can be closed to a ring with the nitrogen atom, possibly with inclusion of a further heteroatom, as described above with reference to R and R and Z is The invention relates to novel substituted s-triazines and a method for their production.

The compounds concerned are of the formula:

Y (5 N zwherein R and R can be the same or different and are selected from the group consisting of hydrogen, alkyl 3,522,255 Patented July 28, 1970 ice of 16 carbon atoms and hydroxy alkyl of 1-6 carbon atoms; Y is selected from the group consisting of -0H3, GHzHa1, -OHHal2, 'CHal Hal, 0 R, SR and wherein Hal is a halogen atom, preferably chlorine, R is selected from the group consisting of alkyl of 1-6 carbon atoms and alkyl of l-6 carbon atoms substituted by OH, OR -NHR N(R or a halogen atom, R and R have the same significance as R and R and furthermore may be closed to a ring, possibly with the inclusion of a further heteroatom, such as a piperazine, piperidine, phenoxazine, 9,10-dihydrophenazine or preferably morpholine ring and R is selected from the group consisting of aryl such as phenyl and alkyl of 1-6 carbon atoms, R taken individually are aryl or alkyl of l to 6 carbon atoms and taken together can be closed to a ring with the nitrogen atom, possibly with inclusion of a further heteroatom, as described above with reference to R and R and Z is wherein R and R have the same significance as above. Preferably, Y is -CH CH Cl, -CHC1 or particularly CCl or also Z.

The new compounds can be prepared by saponifying compounds of the formula (I wherein R is alkyl or hydroxy alkyl of 1-6 carbon atoms or aryl or hydroxy aryl, in the presence of a water misci-- ble organic solvent, especially a lower alkanol, and preferably methanol, and in the presence of about molar quantities of barium hydroxide or sodium hydroxide, potassium hydroxide at a temperature between 0 C. and the boiling point of the solvent, preferably between about 50 and 70 C. to form a compound of Formula I. In the event that Y initially represents the group -CHal the compound can be reacted with an amine of the formula wherein R and R have the same significance as above to form compounds wherein Y is The latter reaction can, for example, be carried out in the presence of an alkali metal alcoholate, preferably in quantities of 0.1 to about 10 wt. percent at room or raised temperatures. In order to facilitate the reaction it is expedient to use a lower alkanol as solvent. It, however, also is possible to use a suificient quantity of the amine that the starting triazine dissolves therein. The ratios of the compounds used, for example, can be between 1:5

and 1:10. If the amine is a solid substance, it can first be dissolved in a small quantity of an organic solvent, such as, for example, acetone, ethyl acetate, dioxane or alkanols. If desired, the reaction can also be carried out in the presence of cathalytic quantities of water or alkali metal hydroxide. The reaction can be carried out at room temperature.

The compounds used as starting materials, for example, can be prepared by the process described in German Pat. 1,189,999.

The compounds according to the invention exhibit biological activity and can be used as herbicides and also, for example, as analgesic and antiphlogistic substances.

The compounds, for example, provide a strong antiphlogistic action on carrageen edema of the rats paw upon oral administration in dosages of 10-100 mg./kg.

The following table indicates the arrest in carrageen edema of the rats paw upon oral administration of 30 mg./kg. of several illustrative compounds according to the invention (results in percent of edema arrest as compared to control group) and the acute toxicity of such compounds. The antiphlogistic action investigations were carried out according to the method of Domenjoz and Cll., Arch. Exp. Pharm. Path., 230, 325 (1957), and the acute toxicity tests were carried out according to the method of Miller & Tainter, Proc. Soc. Exper. Biol. and Med., 57, 261 (1944) with a 24 hour observation period.

D 9220=Z-trichloromethyM-(l-methyl-l-hydroxy)-etl1yl-fi-morpholino-s-triazine. t D 9721=2-ethylamino i-(l-methyl-Lhydroxy)-ethyl-6-piperazino-sriazlne.

D 9722 2-ethylamino-4-(l-methyl-l-hydroxy)-etl1yl 6-piperazin0- hydrochloride-s-triazine.

The following examples will serve to illustrate the compounds according to the invention.

EXAMPLE 1 50 g. of 2-trichloromethyl-4-morpholino-6-[ct-(carbethoxy-oxy)-et-methyl-ethyl]-s-triazine were dissolved in 300 ml. of methanol and the solution heated to boiling. 42 g. of Ba(OH) -8H O were dissolved in 400 ml. of hot methanol and such solution added to the triazine solution over a 3 hour period while the latter was constantly boiled. The triazine solution which initially was clear became cloudy as the saponification proceeded upon addition of the Ba(OH) solution. The reaction mixture was then boiled down without first separating the solids and the residue stirred up with dilute HCl whereupon CO was set free. The Water insoluble portion was taken up in methylene chloride. After such solution had been washed neutral it was boiled down. The residue was triturated with water whereupon it crystallized. The yield of 2 trichloromethyl 4 morpholino 6 (oz methyl-ahydroxy)-ethyl-s-triazine was 18 g. or 43.5% of theory. Its melting point was 7282 C.

EXAMPLE 2 85 g. of 2-trichloromethyl-4-ethylamino-6-[ct-(carbethoxy-oxy)-ot-methyl-ethyl]-s-triazine were dissolved in 300 ml. of methanol and heated to boiling.

72 g. of Ba(OH)- were dissolved in 400 ml. of hot methanol and the non-dissolved BaCO; filtered oil. This solution was then added to the boiling triazine solution over a 3 hour period. The processing thereafter was as in Example 1. 51 g. or a yield 75% of the theory was obtained as the crystalline residue. When recrystallized from ligroin the 2-trichloromethyl-4-ethylamino-6-(amethyl-u-hydroxy)-ethyl-s-triazine of a M.P. of 80-82 C. was obtained.

4 EXAMPLE 3 100 g. of 2-[u-(carbethoxy-oxy)-a-methyl-ethyl]-4- ethanolamino-6-trichloromethyl-s-triazine were dissolved in 180 ml. of methanol. Then a solution of 93 g. of Ba (OH) -8H O in 700 ml. of methanol were added thereto and the mixture heated to reflux with stirring for 1 /2 hours. The reaction solution was then adjusted to a pH of 5 with concentrated HCl whereby CO was liberated and the solution concentrated under vacuum. The residue was stirred up with water whereby 46.8 g. of pure 2-(a-methyla hydroxy) ethyl 4-ethanolamino-6-trichloromethyl-striazine with 1 mol of H 0 were obtained. Yield 52% of theory, M.P. 6974 C.

EXAMPLE 4 114 g. of 2-[a-(carbomethoxy-oxy-a-methyDethyl]- 4 morpholino 6 trichloromethyl s triazine (M.P. C.) were dissolved in 500 ml. of methanol and a solution of 90 g. of Ba(OH) -8H O in 750 ml. of methanol added thereto over a 30 minute period. The mixture was then refluxed for 1 /2 hours. The processing was described in Example 3.

Yield 51 g. of 2-(a-methyl-a-hydroxy)-ethyl-4-morpholino-6-trichloromethyl-s-triazine.

EXAMPLE 5 Analogously the following compounds (a) 2-(a-hydroxy-a-methyl)-ethyl-4-(3-methoxypropyl)- amino-6-trichloromethyl-s-triazine (M.P. 4l-43 C.)

(b) 2-(a-hydroxy-u-methyl)-ethyl-4-piperidino-6-trichloromethyl-s-triazine (M.P. 82-87 C.)

(c) 2-(ahydroxy-a-methyl)-ethyl-4-(2-hydroxypropyl)- amino-6-trichloromethyl-s-triazine (syrup) were respectively obtained from (a) 2- [a- (carbomethoxy-oxy-a-methyl) ethyl] -4-(3 methoxypropylamino-6-trichloromethyl-s-triazine (b Z-[a-(carbomethoxy-oxy-a-methyDethyI] -4-piperidino- 6-trichloron1ethyl-s-triazine c) 2-[oc-(carbomethoxy-oxy-a-methyl)-ethyl] -4-(2)- hydroxypropylamino-6-trichloromethyl-s-triazine EXAMPLE 6 77.5 g. of 2-[a-(carbomethoxy-oxy)-a-methyl-ethyl]-4- (3 hydroxy) propylamino 6-trichloromethyl-s-triazine were heated with 145 ml. of thionyl chloride to produce 2 [ucarbomethoxy-oxy) -ot-methyl-ethyl] -4- 3 -chloropropylamino-6-trichloromethyl-s-triazine, which was not isolated, but processed in the usual manner as a crude product, which was dissolved in ml. of methanol and heated under reflux for 90 minutes with 63 g. of Ba(OH) -8H O dissolved in 5 30 ml. of methanol. After processing as described above, 34 g. or 54% of theory of Z-(ahydroxy a methyl) ethyl -4-(3)-chloropropylamino-6- trichloromethyl-s-triazine of a MP. of 68-71" C. were obtained.

EXAMPLE 7 41.25 g. of 2-[ot-(carboethoxy-oxy)-tx-methyl-ethyl] 4- piperazino-6-trichloromethyl-s-triazine (0.1 mol) were heated to reflux with 161.6 g. (1.8 mols) 50 RC. aqueous ethylamine for 4 hours.

The reaction solution was then concentrated under vacuum and the residue dissolved in 200 ml. of methylene chloride. The solution was washed with water to extract the residue of ethylamine. Then the solution had been concentrated under vacuum. The residue yielded 22.3 g. of 2- [a-(carbethoxy-oxy) -a-methyl-ethyl] -4-piperazino-6-ethylamino-s-triazine which was 66% of theory. Its melting point was 9497 C.

EXAMPLE 8 33.8 g. of 2-[ut-(carbethoxy-oxy)-u-methyl-ethyl]-4-piperazino 6-ethylamino-s-triazine (0.1 mol) were dissolved in 500 m1. of methanol and then a solution of 10 g. of

sodium hydroxyd in 50 ml. water Was-added. After keeping at room temperature for two days the solid Na CO formed was separated and the solution concentrated under vacuum. The residue was dissolved with 200 m1. of ethyl acetate and after Washing with water the solution ing to Example 7 from 2-(a-carbethoxy-oxy-a-methyl) ethyl- 4 -N' methyl piperazino 6 trichloromethyl s triazine, melting point 95-98) were dissolved in 500 ml. of methanol and refluxed with 31.5 g. of Ba(OH -8H O (0.1 mol) for two hours. After coolwas boiled down. 5 ing down 7.3 g. of gaseous HCl (0.2 mol) was added The residue yielded 20.75 g. of 2-(a-methyl-a-hydroxy)- whereupon CO Was set free. The solution was concenl -p l ethylamino-s-triazine which was 78% trated and the residue heated with 200 ml. of ethanol for of theory. Its melting point was 8892 C. two hours whereupon the saponified triazine compound EXAMPLE 10 was dissolved. The solid BaCl was separated and the solutlon concentrated under vacuum. The residue was 26.6 g. of 2-( m-I nethy -u-hydroxy)-ethyl-4-p1peraz1no-6- washed with Water and dried ethylamino-s-tnazlne (0.1 mol) were dissolved m 200 ml. The yield f z of ethyl acetate and 3.65 g. of gaseous HCl (0.1 mol) were piperazino 6 ethylamino s triazine was 201 (95% or introduced. The formed solid of hydrogenchlonde of the 15 713% f theory Its melting Point is triazine compound was SFPaTated and Washed Wlth ethyl The following table gives the formulae of the starting acetate and thereafter dnedmaterials and products of the examples. For sake of sim- The yield of 2-(a-methyl a hydroxy)-ethyl-4-p1perplicity, the triazine ring azino-6-ethylamino-s-triazine hydrogenchloride was 25.6 I of 84.6 of theory. Its melting point under decomposi- 2O N=C\ tion was 281-85 c. N

EXAMPLE 10 E 36.2 g. of 2-[a-(carbethoxy-oxy)-a-methyl-ethy1]-4-N'- methyl-piperazino-6-ethylamino-s-triazine (0.1 mol, vis- 25 W111 be represented therein by the Symbol cous, produced according to Example 7 from 2-(m-carbethoxy oxy a-methyl-ethyl)-4-N'-methyl-piperazino-6- ethylamino-s-triazine (0.1 mol, viscous, produced accord- TABLE Example Starting Material End Product /C(CH5)2OCOC;H5 C(CHQa-OTI 1 O13C 0130-4 \N H 0 \N/ H 0 C(GHQzOfiOCgH a O(OH2)2OH 0 2 Cl3C-- 0130- \NHCQILI, NHCgH C(CHQEOEOCZH C(CHmOH Imam-onion NHCH2-CH2OH /C(OH5)20(|JOCH3 0 01195011 4 013co15o T \N/ n o N H o C(CHQQOCOCHQ C(OH3)2OH 0 5E1 C13C Cl3C NHCH2CH -CH2OCH NHon2-cH. 0H2-ocr1 C(GHMOEO'CH; C(CH3)2OH 5b "0130- (31 0-4 N H N H ownmoooon; 0 0119503 5C Cl3C l imam-omen CH;

TABLE-.Coutinued Example Starting Material End Product C(CH3)20C-OCH3 C(CHa)2OH I 6 C1aC cnc- NIICHz-CHz-ClIgOH NHCHz-Cllz-CIIzCI C(CH )2Ol(l3OC H C(CHahOCOCzII o 7 (11 -4 115c2uN N H Nu N H NH /C(CH3)20|COC2II5 C(CH3)2OII s H CgHN- I II5C2HN% N H NlI N H NH C(CHghOl-I C(OHa)2OH 0 H5CHN- H C2HN N H Nit N H NH-HOl C(OHQzOfiOCzH C(CHmOH 0 1o H CZNH- HsC2HN-4 \N H N-CH, N H NEH;

I claim: 2. The substituted s-triazine of claim 1 which has the 1. A substituted s-triazine of the formula formula l C N R1 5 n b f H R X=N- o OH Z C\ N R2 N R wherein X=N- is selected from the group consistlng of R3 wherein each of R and R are selected from the group and consisting of hydrogen, lower alkyl of 1 to 6 carbon atoms R J and lower hydroxy alkyl of 1 to 6 carbon atoms, Y is selected from the group consisting of -CH:;, CH2Hal, CHHal2, CHalz, -Hal, -0 R, -SR

and

wherein R is selected from the group consisting of hydrogen, lower alkyl of l to 6 carbon atoms and lower alkyl of 1 to 6 carbon atoms substituted with a substituent selected from the group consisting of OH, -OR -NHR N(R and Hal, Hal signifies a halogen atom, R and R have the same meaning as R and may be the same or different with the proviso that only one of these two radicals shall be said substituted alkyl and wherein R and R together may form cyclohexyl, piperazino, N'-methyl-piperazino or piperidino, R is selected from the group consisting of phenyl and lower alkyl of 1 to 6 carbon atoms, R is selected from the group consisting of wherein R and R have the same significance as above; and their pharmaceutically acceptable acid addition salts.

in which each of R and R are selected from the group consisting of hydrogen, lower alkyl of 1 to 6 carbon atoms and lower alkyl of 1 to 6 carbon atoms substituted by a member selected from the group consisting of References Cited UNITED STATES PATENTS 2,887,409 5/1959 Van Loo 260-249.9 XR 2,926,165 2/1960 Shapiro et al. 260-2499 HENRY R. JILES, Primary Examiner J. M. FORD, Assistant Examiner US. Cl. X.R. 260-249.5, 999 

